Behavioral and electroencephalographic analyses of the central effects of sulfamethoxazole (5- methy 1-3-sulphanilamido-isoxazole) (SMX), trimethoprim [2, 4-diamino-5- (3, 4, 5-trimethoxy benzyl) pyrimidine] (TMP), and their mixture in a ratio of 5 : 1 (SMX-TMP) were carried out in animal experiments. Each drug was orally administered in a gum-emulsion.
1. SMX-TMP (6000-9000 mg/kg) caused suppression of somatic behavior in mice viz; inhibition of spontaneous locomotor activity, slowing down of movement, and abnormal posture. The animals died under tonic extensor. The behavioral changes caused by 4000-6000 mg/kg of SMX were almost the same as those by SMX-TMP. With 3000-9000 mg/kg of TMP, marked muscle relaxation accompanied by slowing down of movement and abnormal posture was observed. The animals died in respiratory paralysis. In cats, each drug, at doses of 25-50 times the human dosage, caused sedative behavior and inhibition of appetite. Vomitting appeared with 900 mg/kg of SMX-TMP.
2. The LD50 in mice was as follows : SMX-TMP : 5513 mg/kg, TMP : 7000 mg/kg, SMX : 3662 mg/kg.
3. The grip strength test, rotarod performance test and righting reflex in mice were not influenced by 1000 mg/kg of each drug.
4. Neither drug at a dose of 1000 mg/kg possessed analgesic activity when evaluated by the stretching method and the modified HAFFNER'S method, nor anti-convulsive activity on evaluation by the maximal electroshock method and the pentetrazol seizure method in mice.
5. Each drug showed hypothermic activity in mice, the effect of TMP being the most marked. 6. The nondiscriminated avoidance response in rats was remarkably suppressed by TMP and slightly suppressed by SMX-TMP. The effect of SMX on the response was negligibly small.
7. The potentiation of thiopental-Na anaesthesia was the most evident with SMX; the lesser effects of SMX-TMP and TMP were almost the same as each other.
8. SMX-TMP and TMP caused sedate behavior in chronically electrodes-implanted cats and increased the resting pattern for several hours. Even with a large dose of SMX-TMP, no essential changes of EEG pattern were observed in any EEG-leads, except for a slight inhibition of the slow wave components at the amygdala and the hippocampus in the slow wave sleeping state.
9. The sleep-wakefulness cycles of cats were remarkably altered by SMX-TMP and/or TMP, an increase in the waking state, and decrease in the slow and fast wave sleeping states, being observed. These effects were considered to be primarily caused by TMP.
